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is a selective therapeutic modality that combines an oxygen rich environment and a light source that stimulates a photosensitizing agent to produce singlet oxygen which is highly toxic to the cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">16&#44;17</span></a> Porphyrins and particularly hematoporphyrins &#40;e&#46;g&#46;&#58; photofrin&#41; were the first intravenous substances used for PDT&#44; characterized by their long-term accumulation in target tissue that required rigorous photoprotection for several weeks after administration&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">17</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In 1990 new topical porphyrins such as 5-aminolevulinic acid &#40;ALA&#41; or its methyl ester &#40;MAL&#41; emerged&#44; which could both easily penetrate the epidermis and produce short-term circumscribed photosensitivity&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">18</span></a> More recently&#44; hexylester 5-aminolevulinate &#40;HAL&#41; has been proposed to induce formation of high concentrations of PpIX in neoplastic tissue&#44; but its use is still experimental&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">19</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">These molecules intervene in heme biosynthesis intracellular pathway&#44; by inducing the formation of a photoactive porphyrin known as protoporphyrin IX &#40;PpIX&#41;&#44; which is an efficient photosensitizer that accumulates particularly in photodamaged skin&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">17</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">PDT requires either an incoherent&#47;coherent light source that should be ideally specific to the chromophore&#47;photosensitizer used&#46; Incoherent light devices include a continuous-wave red light &#40;635<span class="elsevierStyleHsp" style=""></span>nm&#41;&#44; blue light &#40;417<span class="elsevierStyleHsp" style=""></span>nm&#41; and intense-pulsed light &#40;IPL&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">20</span></a> whereas lasers are among the most used coherent light equipment&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">20</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">As photosensitizers can either localize in lysosomes&#44; mitochondria&#44; Golgi apparatus&#44; endoplasmic reticulum&#44; and plasma membranes&#44; PDT effects are a consequence of how PS interact with cells within the target tissue&#47;organ or tumor&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">21&#44;22</span></a> Moreover&#44; it seems that PDT direct DNA cellular damage can occur via modifications of guanine moiety and through strand breaks at uracil and thymine sites&#44; whereas indirect DNA disruption is explained by deactivation of repairing enzymes by free radicals and singlet oxygen production&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">23</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">In addition&#44; skin effects of topical PDT include solar elastosis improvement and neocollagenesis via the induction of expression of collagen type I&#47;III production&#44; MMP-1&#44;-3&#44;-9 and-12 down-regulation&#44; and TGF &#946; up-regulation&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">10&#44;24</span></a> Photodynamic therapy with MAL has also been reported to increase dermal thickness and to improve collagen&#44; elastic tissue and perifollicular fibrosis in treated skin&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">25&#44;26</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Several procedures have been used for actinic damage treatment &#40;e&#46;g&#46;&#58; chemical exfoliation&#44; topical retinoids&#44; lasers&#44; intense pulsed light &#40;IPL&#41; and LEDs &#40;light emitting diodes&#41;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">24&#44;27&#8211;34</span></a> However&#44; and according to a systematic review&#44; there is limited scientific evidence to support the preferential use of any of these therapies in photodamaged skin&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">35</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Up to know&#44; topical PDT use in the treatment of photodamage is still off-label&#46; Therefore&#44; as uncertainty still remains in this field&#44; this paper aims to assess published scientific evidence to establish the efficacy and safety of such therapy&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Search strategies</span><p id="par0055" class="elsevierStylePara elsevierViewall">We aimed to identify all relevant published or unpublished RCTs regardless of language&#46; Searches were performed during the last 10 years&#44; and updated up to 4 May 2016&#46; Search terms with results are depicted in Supplementary Material 1&#46; Trial registries were scanned up to December 15&#44; 2015&#44; using the search terms&#58; &#8220;photodamage&#8221;&#44; &#8220;photoaging&#8221;&#44; &#8220;photodynamic therapy&#8221; and &#8220;photodynamic rejuvenation&#8221; &#40;Supplementary Material 2&#41;&#46; We also checked for relevant references in included and excluded studies&#46; If full text of the articles was not available&#44; we tried to contact authors&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">We did not perform a separate search for adverse effects of the specified intervention&#46; However&#44; we examined data on adverse effects from all included studies&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Inclusion criteria</span><p id="par0065" class="elsevierStylePara elsevierViewall">All parallel randomized controlled trials &#40;RCTs&#41; of PDT for facial photodamage &#40;dermatoheliosis&#41;&#47;photoaging and&#47;or photodynamic rejuvenation that included adult participants diagnosed with facial photodamage &#40;dermatoheliosis&#41; or photoaging&#44; and who have been treated with any PDT-based rejuvenation procedure&#44; were included&#46; Any photodynamic-based intervention for photodamage &#40;dermatoheliosis&#41; or photoaging was considered&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Types of outcomes measures</span><p id="par0070" class="elsevierStylePara elsevierViewall">Primary endpoints included&#58; &#40;1&#41; the proportion of participants who had an improvement&#47;failure in global facial photodamage&#59; &#40;2&#41; quality of life &#40;QoL&#41; changes measured through any validated and recognized generic or disease-specific instrument&#59; &#40;3&#41; any adverse events&#44; safety and tolerability&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Secondary outcomes corresponded to&#58; &#40;1&#41; the proportion of participants who had an improvement&#47;failure in facial hyperpigmentation&#44; wrinkles&#44; sallowness&#44; erythema or roughness according to a validated and&#47;or recognized generic or disease-specific instrument&#59; &#40;2&#41; change in facial cosmetic appearance&#59; &#40;3&#41; participant satisfaction&#59; &#40;4&#41; pain evaluation after the photodynamic-based procedure&#44; and &#40;5&#41; cost effectiveness studies&#44; if available&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Data extraction and synthesis</span><p id="par0080" class="elsevierStylePara elsevierViewall">Four authors &#40;V&#46;R&#46;&#44; J&#46;M&#46;&#44; A-P F&#46;&#44; G&#46; S&#46;&#41; checked the searched titles and abstracts&#46; Potentially relevant studies were selected for full-text review&#46; All authors independently assessed whether each study met the predefined selection criteria&#44; and differences were resolved by discussion&#46; The same four authors performed data extraction in pre-established data collection formats and independently assessed the risk of bias of included studies as low&#44; high or unclear according to a domain-based evaluation described in the <span class="elsevierStyleItalic">Cochrane Handbook for Systematic Reviews of Interventions</span><a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">36</span></a> &#40;e&#46;g&#46;&#58; &#8216;sequence generation&#8217;&#59; &#8216;allocation concealment&#8217;&#59; &#8216;blinding&#8217;&#59; &#8216;outcome data&#8217;&#59; &#8216;selective reporting&#8217; and other sources of bias&#41; that could put it at high risk of bias &#40;e&#46;g&#46; baseline imbalance&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Statistical issues</span><p id="par0085" class="elsevierStylePara elsevierViewall">We planned to include only parallel designed trials&#46; Dichotomous outcomes data were presented as reported in each individual study&#46; However&#44; if sufficient data were available&#44; outcomes data were presented as relative risks &#40;RR&#41; with their associated 95&#37; confidence intervals &#40;CIs&#41; and analyzed them in the Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#44; using the Mantel&#8211;Haenszel test&#44; unless we stated otherwise&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">We re-analyzed the data originally described according to an intention to treat &#40;ITT&#41; principle&#44; whenever possible&#46; If study authors conducted a per-protocol analysis&#44; we evaluated potential imbalances in the dropout rate between the trial arms to determine bias&#46; If treatment by allocation population was unavailable&#44; we used an available case population and reported this accordingly&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">We planned to evaluate clinical&#44; statistical&#44; and methodological heterogeneity&#46; Statistical heterogeneity was planned to be tested by using the <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span> statistic&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">36</span></a> If substantial heterogeneity &#40;<span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span> greater than 60&#37;&#41; was found for the primary outcomes&#44; we planned to explore reasons for heterogeneity&#46; As at least ten studies suitable for meta-analysis were needed for funnel plot asymmetry testing&#44;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">37</span></a> we were unable to perform such test&#46; Also&#44; as we were unable to identify an adequate number of homogenous studies &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>3&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">38</span></a> we did not perform a meta-analysis but we summarized the data for each trial qualitatively&#46; The number of studies was also inadequate to perform subgroup and sensitivity analysis&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Studies description</span><p id="par0100" class="elsevierStylePara elsevierViewall">After removal of duplicates our searches retrieved 1293 references&#46; Further to titles and abstracts examination&#44; we excluded 1235 references from the review&#46; We obtained full-text copies of the remaining 51 records for further evaluation&#44; and after evaluation&#44; 39 studies were excluded&#46; Reasons for their exclusion are depicted in Supplementary Material 3&#46; Exclusions were made only after assessment of the full-text reports&#46; The most frequent reason for exclusion was that they were non-RCTs&#46; Regarding ongoing studies&#44; we only identified one ongoing study&#44; which is in the recruiting phase &#40;Supplementary Material 3&#41;&#46; Re-analysis of retrieved data was not necessary&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">All retrieved studies were published in English&#46; Thirteen references to 12 studies were finally included&#44; as one same trial had two reports<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">25&#44;39</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; A total of 286 participants &#40;135 patients from ALA studies and 151 from MAL studies&#41; were evaluated&#46; Among these&#44; 30 were men and 212 women&#44; but in 2 studies&#44; gender of participants was not specified<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;40</span></a> &#40;Supplementary Material 4&#41;&#46; The age of the participants ranged from 35 to 82 years&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">Among all 12 included randomized trials&#44; 6 studies used ALA and 6 MAL&#44; as chromophores&#46; Only 2 studies used a placebo as control<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41</span></a> and 10 had an active control treatment arm&#46; Studies were published from year 2004 until 2015&#46; Four studies were conducted in the USA&#44;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;42&#8211;44</span></a> four in South America&#44;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#8211;41&#44;45</span></a> 2 in Spain&#44;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">27&#44;46</span></a> 1 in Denmark&#44;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">47</span></a> and one in China&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">48</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">The range number of participants included in the individual studies varied from 4 to 60 participants&#46; Ten studies had a split-face design whereas 2 had a full-face design&#46; All patients were diagnosed with mild to severe facial photodamage&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The included studies evaluated the following interventions&#58; &#40;1&#41; IPL vs IPL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>5-ALA in a split-face design<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;44&#44;48</span></a>&#59; &#40;2&#41; laser fractional resurfacing alone vs laser fractional resurfacing<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light in a split-face design<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">46</span></a>&#59; &#40;3&#41; MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light with 1<span class="elsevierStyleHsp" style=""></span>h incubation vs MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light with 3<span class="elsevierStyleHsp" style=""></span>h incubation in a split-face design<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">27</span></a>&#59; &#40;4&#41; IPL waveband from 530 to 750<span class="elsevierStyleHsp" style=""></span>nm and short pulse durations &#40;J&#47;cm<span class="elsevierStyleSup">2</span>&#44; 2&#8211;2&#46;5<span class="elsevierStyleHsp" style=""></span>ms&#44; delay 10<span class="elsevierStyleHsp" style=""></span>ms&#41;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>0&#46;5&#37; liposome encapsulated vs IPL &#40;waveband from 400 to 720<span class="elsevierStyleHsp" style=""></span>nm&#41;&#44; three passes were performed &#40;3&#46;5<span class="elsevierStyleHsp" style=""></span>J&#47;cm<span class="elsevierStyleSup">2</span>&#44; 30<span class="elsevierStyleHsp" style=""></span>ms pulse duration&#41;&#44; also in a split-face design<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">47</span></a>&#59; &#40;5&#41; blue light at different incubation times<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>5-ALA in a split-face design<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">42</span></a>&#59; &#40;6&#41; IPL vs IPL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>5-ALA in a full-face design<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">40</span></a>&#59; &#40;7&#41; MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light with 3<span class="elsevierStyleHsp" style=""></span>h incubation vs placebo<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light with 3<span class="elsevierStyleHsp" style=""></span>h incubation in a split-face design<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">39</span></a>&#59; &#40;8&#41; MAL with 1<span class="elsevierStyleHsp" style=""></span>h incubation<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light vs MAL with 1<span class="elsevierStyleHsp" style=""></span>h incubation<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>blue light in a split-face design<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">43</span></a>&#59; &#40;9&#41; MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light vs MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1&#46;5<span class="elsevierStyleHsp" style=""></span>mm length micro-needling in a split-face design<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">45</span></a>&#59; and &#40;10&#41; MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>h daylight exposure vs placebo<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>h daylight exposure in a full-face design&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">41</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The majority of included studies &#40;except two<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41</span></a>&#41; did not specify primary and secondary outcomes&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Facial photodamage assessment was performed by the use of several original or modified scales such the Griffith&#39;s&#44; Dover&#39;s&#44; Fitzpatrick&#39;s&#44; or arbitrary scales&#46; Four studies reported that they had applied a &#8220;modified version&#8221; of another previous developed scale&#44;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41&#44;45&#44;48</span></a> but authors did not provide details of how and if their &#8220;modified version&#8221; was tested prior to its use&#46; Only one study assessed intervention&#39;s effects on quality of life &#40;QoL&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">41</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">A large proportion of the trials &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#41; assessed intervention-associated adverse events <span class="elsevierStyleItalic">a priori</span>&#44; either through questionnaires that rated the treatment tolerability&#44; or as skin reactions&#44; such as erythema&#44; dryness&#44; edema&#44; oozing&#44; vesiculation&#44; crusting&#44; pigmentation disturbances&#44; skin atrophy&#44; scarring and desquamation or scaling&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">28</span></a> In addition&#44; several included studies assessed secondary outcomes&#44; but overall&#44; the methods used for measurement and the timing of the assessments were not uniform or clear&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Risk of bias Assessment</span><p id="par0140" class="elsevierStylePara elsevierViewall">Risk of bias for each included study and graphs are depicted in Supplementary Material 4&#44; and <a class="elsevierStyleCrossRefs" href="#fig0010">Figs&#46; 2 and 3</a>&#44; respectively&#46; As one of the reviewers &#40;GS&#41; was the main author of 2 studies&#44; both studies were assessed only by the other 3 assessors&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0145" class="elsevierStylePara elsevierViewall">We assessed the global risk of bias for each included study&#44; and we considered two studies to be at &#8220;low risk of bias&#8221; as both met all criteria across all domains in the Cochrane &#8220;Risk of bias&#8221; assessment tool &#40;plausible bias unlikely to seriously alter the results&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41</span></a> We rated the remaining 10 studies as at &#8220;unclear risk of bias&#8221; &#40;plausible bias that raises some doubt about the result&#41; because one or more criteria were assessed as unclear &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">An important number of included studies &#40;9&#41; provided insufficient detail to enable us to make accurate judgements in respect to the domain &#8220;concealment of the allocation sequence&#8221;&#46;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">27&#44;28&#44;40&#44;42&#8211;44&#44;46&#8211;48</span></a> Indeed&#44; intervention allocations masking through sequentially numbered&#44; opaque&#44; sealed envelopes or pharmacy-controlled allocation was only performed in 2 studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41</span></a> Similarly&#44; the &#8220;blinding of outcome assessors&#8221; domain was unclear in 5 studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">27&#44;40&#44;42&#44;47&#44;48</span></a> and only two studies described blinding of study participants and personnel in sufficient detail&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41</span></a> Also&#44; baseline characteristics of patients or groups were only described in 3 studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41&#44;43</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">Incomplete data of patients lost to follow-up&#44; and subsequent per-protocol analyses were other important sources of potential bias in a number of the included studies&#46; In addition&#44; trial protocol was provided in only two studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41</span></a> Judgements were amended as required&#44; after contact with trial investigator&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">45</span></a> In some other studies authors replied that they no longer had information regarding trial methods<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">42</span></a> and for other studies&#44; we did not obtain a reply from authors&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Effects of interventions</span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">5-ALA</span><p id="par0160" class="elsevierStylePara elsevierViewall">Although 6 studies evaluated the effect of 5-ALA as chromophore&#44; either insufficient data or just baseline vs post-treatment comparisons limited relative risks calculations which could be performed only for 3 studies<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;47&#44;48</span></a> &#40;<a class="elsevierStyleCrossRefs" href="#fig0020">Figs&#46; 4&#8211;6</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="fig0030"></elsevierMultimedia><p id="par0165" class="elsevierStylePara elsevierViewall">In general&#44; there was a tendency to less treatment failure in ALA-treated split-faces&#46; Also&#44; we were unable to determine primary and secondary endpoints in all 5-ALA studies&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">The effect of ALA in actinic keratosis&#44; as well as in facial photodamage was assessed in 2 studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">40&#44;42</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Investigator assessment of changes in facial photodamage and participant&#39;s photodamage evaluation were performed through digital standardized photographs in 3 studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">40&#44;44&#44;47</span></a> and two studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;48</span></a> respectively&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Partial or full sponsoring of ALA trials by the pharmaceutical industry was detected in 4 studies<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;40&#44;42&#44;48</span></a> and in 2 studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">44&#44;47</span></a> sponsoring information was lacking&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Photodamage results according to the timeline at which outcomes were assessed in ALA studies varied from 1 month after last session<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;42</span></a>&#44; 2 months after last session&#44;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">40</span></a> 1&#8211;2 months after last session&#44;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">48</span></a> 3 months after last session&#44;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">47</span></a> and at 1&#44; 3 and 6 months&#44; after last session&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">44</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">Regarding patient related outcomes&#44; subject satisfaction was evaluated in 4 out of 6 ALA studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;42&#44;47&#44;48</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">In general&#44; more erythema&#44; edema and desquamation were reported in the ALA-treated side of the face&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">5-ALA-related adverse events</span><p id="par0200" class="elsevierStylePara elsevierViewall">Herpes simplex reactivation and post-inflammatory hyperpigmentation were reported in Touma et al&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">42</span></a> and in Xi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">48</span></a> studies&#44; respectively&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">A summary of findings table of 5-ALA results according to GRADE standards is depicted in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">MAL</span><p id="par0210" class="elsevierStylePara elsevierViewall">Although 6 studies evaluated the effect of MAL as chromophore&#44; the lack of contralateral comparisons or insufficient data allowed the calculation of relative risks only for 4 out of 6 studies &#40;<a class="elsevierStyleCrossRefs" href="#fig0050">Figs&#46; 7&#8211;10</a>&#41;&#46;</p><elsevierMultimedia ident="fig0050"></elsevierMultimedia><elsevierMultimedia ident="fig0035"></elsevierMultimedia><elsevierMultimedia ident="fig0040"></elsevierMultimedia><elsevierMultimedia ident="fig0055"></elsevierMultimedia><p id="par0215" class="elsevierStylePara elsevierViewall">We also were unable to differentiate primary and secondary endpoints in 4 out of 6 studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">27&#44;43&#44;45&#44;46</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">The effect of MAL&#44; actinic keratosis&#44; and in facial photodamage simultaneously was assessed in 2 studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">43&#44;45</span></a> Investigator assessment of photodamage outcomes was performed through digital standardized photographs in 1 study&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">43</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">In general&#44; timelines for photodamage outcome evaluation in MAL trials ranged from 1 to 3 months after last session&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">Partial or full sponsoring of trials by the pharmaceutical industry was detected in 3 studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41&#44;43</span></a> Sponsoring details were not described in 2 studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">27&#44;46</span></a> and one study was developed without any sponsor&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">45</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">In respect to patient satisfaction&#44; such outcome was evaluated in 3 studies with better satisfaction scores in the MAL treated split-face&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;43&#44;46</span></a> In addition&#44; just 1 out of the 12 studies &#40;ALA and MAL&#41; included a quality of life outcome&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">41</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">Overall&#44; erythema&#44; edema and desquamation were more frequently reported in the side of the face that included MAL as chromophore in all studies&#44; except in one study<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">43</span></a> in which no statistical differences between the use of blue vs red light were found&#44; but also mild discomfort was more frequent with red-light exposure&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">MAL-related adverse events</span><p id="par0245" class="elsevierStylePara elsevierViewall">Herpes simplex reactivation was reported in two studies whereas post-inflammatory hyperpigmentation was described in 3 studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41&#44;46</span></a> A severe infection related to the concomitant use of microdermabrasion<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PDT was reported in 1 out of 10 patients in Torezan et al&#46;&#8217;s<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">45</span></a> study and a severe allergic reaction not related to PDT was reported in another study&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">39</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">A summary of findings table of MAL results according to GRADE standards is depicted in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Discussion</span><p id="par0255" class="elsevierStylePara elsevierViewall">To the best of our knowledge&#44; this is the first published systematic review &#40;SR&#41; to assess and examine the evidence for the efficacy and safety of PDT in facial photodamage&#44; and although the full protocol of this SR was not published &#40;just its abstract&#41;&#44; it is available upon request to correspondence author&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">Two high quality studies suggest that MAL-PDT is effective in the treatment of facial photodamage&#44; but low to moderate quality of evidence shows that PDT with ALA seems to be also effective&#46; Although adverse events &#40;AEs&#41; were reported inadequately in most studies&#44; non-serious reported AEs include herpes simplex recurrence and post-inflammatory hyperpigmentation&#44; particularly in studies that included participants with darker skin &#40;3 out of 4 studies with PIH reports&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41&#44;46&#44;48</span></a></p><p id="par0265" class="elsevierStylePara elsevierViewall">The main objectives of a randomized clinical trial are to assess efficacy and safety of an intervention&#46; In this respect&#44; concealment and blinding are key domains in the assessment of risk of bias&#46;<a class="elsevierStyleCrossRefs" href="#bib0520"><span class="elsevierStyleSup">49&#8211;51</span></a> In particular&#44; the methods used to generate the allocation sequence and how the sequence was concealed&#44; are the most important and sensitive indicators that bias has been minimized in a clinical trial&#44; as participants and investigators are masked to the upcoming assignment&#44; and therefore could not &#8220;manipulate&#8221; it&#46; Also&#44; standardization of outcomes and objective measurement are key elements not only for clinical decision making&#44; but also to establish health policies&#46;<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">52&#8211;54</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">Overall&#44; the evidence provided by this review was limited mainly due to outcome inconsistencies&#44; the lack of description of randomization methods&#47;sequence generation&#44; and a lack of a double-blind trial design&#46; Moreover&#44; the high heterogeneity of studies did not allow a quantitative synthesis of the evidence found&#46; However&#44; there was a tendency for having a better result when PDT with any chromophore was used&#44; when compared to the use of a light source alone&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">Most of the included studies in this review were performed before the requirement of trial registration&#46; As a result of insufficient data and the lack of reporting&#44; we were &#8220;forced&#8221; to downgrade the quality of evidence to &#8220;unclear risk of bias&#8221;&#44; as we appraised these studies according to the information contained within the full text of each article&#46; However&#44; more unbiased judgment elements could have been obtained if we were able to get a reply from all authors&#44; but such information could only be gathered from one main author&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall">In this review&#44; it is unlikely that we have missed studies with an important sample size as we performed a rigorous systematic search of published and unpublished literature and we also tried to contact leading experts&#46; Nonetheless&#44; we cannot absolutely rule out the influence of publication bias&#46; Unfortunately we were unable to reliably assess the presence of publication bias&#44; given the small number of included studies&#46; Also&#44; we attempted to lower potential biases in the evaluation of two MAL trials<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41</span></a> performed by one of the reviewers of this systematic review by limiting their assessment only by the other 3 assessors&#46;</p><p id="par0285" class="elsevierStylePara elsevierViewall">The applicability of evidence found by this review corresponds to what is usual in clinical practice&#44;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">4&#44;55</span></a> as included trials covered the usual age spectrum of participants who seek a dermatologist for photodamage therapeutic options&#46; However&#44; it is important to bear in mind that depending on the severity of facial photodamage&#44; patients over 70 years old might not be the best candidates for PDT as they often require more invasive procedures such as resurfacing with ablational lasers and&#47;or surgery&#46; Also&#44; as all included studies had participants with Fitzpatrick&#39;s SPT from I through IV&#44; the applicability of the evidence in SPT V-VI is limited&#46; Similarly&#44; results applicability in men could be affected&#44; as the majority of included participants&#44; were women&#46;</p><p id="par0290" class="elsevierStylePara elsevierViewall">In conclusion&#44; the findings in our review showed that MAL PDT was effective for the treatment of facial photodamage&#44; but also have highlighted that only a small number of published trials have followed the Consolidated Standards of Reporting Trials &#40;CONSORT-Statement&#41; and the criteria of evidence-based medicine&#46; Such standards are necessary to heighten evidence strength and quality in future trials design&#46; Also&#44; as there is a relative paucity of long-term evaluations of the effect of PDT in facial photodamage and in quality of life&#44; such knowledge gaps deserve further research&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Sponsoring</span><p id="par0295" class="elsevierStylePara elsevierViewall">This work was supported by the Group of Investigative Dermatology-GRID of the <span class="elsevierStyleGrantSponsor" id="gs1">Universidad de Antioquia</span>&#44; Medellin&#44; Colombia and by the <span class="elsevierStyleGrantSponsor" id="gs2">Fundacion Dermabase</span>&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Conflict of interest</span><p id="par0300" class="elsevierStylePara elsevierViewall">Dr&#46; Gloria Sanclemente has participated in advisory boards and has received honoraria and scientific meeting support from Galderma Laboratories&#46;</p><p id="par0305" class="elsevierStylePara elsevierViewall">Dr&#46; Veronica Ruiz Ca&#241;as has received scientific meeting support from Galderma Laboratories&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall">Dr&#46; Jenny Marcela Miranda Orozco has received scientific meeting support from Galderma Laboratories&#46;</p><p id="par0315" class="elsevierStylePara elsevierViewall">Dr&#46; Alba Patricia Ferr&#237;n Bastidas has received scientific meeting support from Galderma Laboratories&#46;</p><p id="par0320" class="elsevierStylePara elsevierViewall">Paola Andrea Ramirez has nothing to disclose</p><p id="par0325" class="elsevierStylePara elsevierViewall">Gilma Hernandez has nothing to disclose&#46;</p></span></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Photodynamic therapy &#40;PDT&#41; involves the combination of a light source and a photosensitizing agent to induce tissue damage via the generation of singlet oxygen&#46; Although topical PDT has been approved for other indications&#44; its use in facial photodamage is uncertain&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Aims</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">To assess the efficacy and safety of PDT in facial skin photoaging&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Methods</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">All randomized clinical trials &#40;RCTs&#41; evaluating the efficacy and safety of any form of topical PDT for the treatment of facial photodamage &#40;dermatoheliosis&#41; or photoaging in patients older than 18 years&#44; were included&#46; Photodynamic-therapy using any topical photosensitizing agent at any dose&#44; and with any light-source&#44; were considered&#46; Comparators were chemical exfoliation&#44; intense pulsed light &#40;IPL&#41;&#44; light emitting diodes &#40;LED&#41;&#44; dermabrasion or microdermabrasion&#44; ablative or non-ablative lasers&#44; injectables&#44; surgery&#44; placebo and&#47;or no treatment&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">A systematic search in PubMed&#44; Embase&#44; Lilacs&#44; Google Scholar and RCT&#39;s registry databases&#44; was performed&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Results</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Search was conducted up to May 4th 2016&#46; Four authors independently selected and assessed methodological quality of each RCT&#46; According to inclusion criteria&#44; twelve studies were included &#40;6 aminolevulinate &#40;ALA&#41; trials and 6 methyl aminolevulinate &#40;MAL&#41; trials&#41;&#44; but the majority of them had methodological constraints particularly in randomization description and patients&#47;outcome assessors blindness&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Discussion and conclusions</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Overall results indicated that PDT either with ALA or with MAL was effective and safe for facial photodamage treatment&#44; but high quality of evidence was found mainly for MAL studies&#46;</p></span>"
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        "resumen" => "<span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Introducci&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La terapia fotodin&#225;mica &#40;TF&#41; incluye una combinaci&#243;n de una fuente de luz y un agente fotosensibilizante para inducir da&#241;o tisular a trav&#233;s de la generaci&#243;n de ox&#237;geno singlete&#46; Aunque la TF se ha aprobado para otras indicaciones&#44; su uso en el fotoda&#241;o facial resulta incierto&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Objetivo</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Valorar la eficacia y seguridad de la TF en el fotoenvejecimiento de la piel del rostro&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">M&#233;todos</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Se incluyeron todos los ensayos cl&#237;nicos aleatorizados &#40;ECA&#41; que eval&#250;an la eficacia y seguridad de cualquier forma de TF t&#243;pica para el tratamiento del fotoda&#241;o facial &#40;dermatoheliosis&#41; o fotoenvejecimiento en pacientes mayores de 18 a&#241;os&#46; Se consider&#243; la TF que utiliza cualquier dosis de agente fotosensibilizante&#44; as&#237; como cualquier fuente lum&#237;nica&#46; Los comparadores fueron&#58; exfoliaci&#243;n qu&#237;mica&#44; luz pulsada intensa &#40;IPL&#41;&#44; diodo emisor de luz &#40;LED&#41;&#44; dermoabrasi&#243;n o microdermoabrasi&#243;n&#44; l&#225;seres ablativos o no ablativos&#44; inyectables&#44; cirug&#237;a&#44; placebo y&#47;o ausencia de tratamiento&#46;</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Se llev&#243; a cabo una b&#250;squeda sistem&#225;tica en las bases de datos de los registros de PubMed&#44; Embase&#44; Lilacs&#44; Google Scholar y ECA&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Resultados</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">La b&#250;squeda se realiz&#243; hasta el mes de mayo de 2016&#46; Cuatro autores seleccionaron y valoraron de manera independiente la calidad metodol&#243;gica de cada ECA&#46; Con arreglo a los criterios de inclusi&#243;n&#44; se incluyeron 12 estudios &#40;6 ensayos sobre aminolevulinato &#91;ALA&#93; y 6 sobre metiloaminolevulinato &#91;MAL&#93;&#41;&#44; aunque la mayor&#237;a de ellos conten&#237;an limitaciones metodol&#243;gicas&#44; particularmente en cuanto a la descripci&#243;n de la aleatorizaci&#243;n y la valoraci&#243;n a ciegas de los asesores de los pacientes&#47;resultados&#46;</p></span> <span id="abst0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Discusi&#243;n y conclusiones</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Los resultados generales indicaron que la TF&#44; tanto con ALA como con MAL&#44; era una terapia efectiva y segura para el tratamiento del fotoda&#241;o facial&#44; aunque se encontr&#243; evidencia de alta calidad principalmente en los estudios realizados sobre MAL&#46;</p></span>"
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            "titulo" => "Introducci&#243;n"
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            "apendice" => "<p id="par0335" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
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      0 => array:7 [
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          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">PRISMA flow diagram&#46;</p>"
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          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Risk of bias graph&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
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          "en" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Risk of bias summary graph&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
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          "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Forest plot of comparison&#58; 5-ALA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>IPL vs IPL alone&#44; outcome&#58; Global Photodamage failure to improve with <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20 subjects &#40;40 split-faces&#41;&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
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        "tipo" => "MULTIMEDIAFIGURA"
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          "en" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">5-ALA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>IPL vs IPL alone&#44; outcome&#58; 3&#46;1 Failure to improve according to a global score of photoaging &#40;analysis was performed with <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>26 patients &#40;52 splitfaces&#41;&#41;&#46; The 2 patients that were excluded were labeled as not improved in the 5-ALA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>IPL intervention group&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
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        "etiqueta" => "Figure 6"
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        "mostrarFloat" => true
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        "descripcion" => array:1 [
          "en" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Forest plot of comparison&#58; liposome encapsulated 5-ALA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>IPL vs IPL alone&#44; outcome&#58; 5&#46;1 Failure to improve periorbital wrinkles&#46; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>37 subjects &#40;74 splitfaces&#41;&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
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        "etiqueta" => "Figure 7"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
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        "figura" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">Forest plot of comparison&#58; MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>fractional laser vs fractional laser&#44; outcome&#58; 2&#46;1 Failure to achieve good cosmetics results&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
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        "identificador" => "fig0035"
        "etiqueta" => "Figure 8"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
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            "Tamanyo" => 111530
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        "descripcion" => array:1 [
          "en" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">Forest plot of comparison&#58; 3<span class="elsevierStyleHsp" style=""></span>h MAL incubation<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light vs 1<span class="elsevierStyleHsp" style=""></span>h MAL incubation<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light&#44; outcome&#58; 4&#46;1 Failure to improve fine lines&#46; The excluded patient was labeled as a failure in the 1<span class="elsevierStyleHsp" style=""></span>h MAL incubation group&#46; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10 subjects &#40;20 split-faces&#41;&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
        ]
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        "identificador" => "fig0040"
        "etiqueta" => "Figure 9"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">Forest plot of comparison&#58; 6 MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light vs placebo<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light&#44; outcome&#58; 6&#46;1 Global Photodamage failure to improve&#46; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>98 split-faces&#46; The subject who discontinued treatment due to an adverse reaction was labeled as a failure in the MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light group&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
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        "etiqueta" => "Figure 10"
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        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
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          "en" => "<p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">Forest plot of comparison&#58; MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>daylight vs Placebo<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>daylight&#44; outcome&#58; 7&#46;1 Global Photodamage failure to improve&#46; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>60 subjects &#40;60 whole faces&#41;&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Center&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">5-ALA for facial photodamage&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient or population&#58; Facial Photodamage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Setting&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Intervention&#58; 5-ALA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Comparison&#58; Any intervention&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Outcomes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Anticipated absolute effects<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">&#42;</span></a> &#40;95&#37; CI&#41;</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Relative effect &#40;95&#37; CI&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">No&#46; of participants &#40;studies&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Quality of the evidence &#40;GRADE&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Comments&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk with any intervention&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk with 5-ALA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Failure to improve according to a Global Photodamage scale&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">550 per 1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">198 per 1000 &#40;77&#8211;523&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RR 0&#46;36 &#40;0&#46;14&#8211;0&#46;95&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">40 &#40;1 RCT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed&#44; a full recommendation cannot be made&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Failure to improve according to a global score of photoaging&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">154 per 1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">115 per 1000 &#40;29&#8211;466&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RR 0&#46;75 &#40;0&#46;19&#8211;3&#46;03&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">52 &#40;1 RCT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed&#44; a full recommendation cannot be made&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Failure to improve periorbital wrinkles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">378 per 1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">299 per 1000 &#40;155&#8211;568&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RR 0&#46;79 &#40;0&#46;41&#8211;1&#46;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">74 &#40;1 RCT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed&#44; a full recommendation cannot be made&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">The method of sequence generation was not reported&#46; The method used for allocation concealment was not described&#46; It was a single-blinded &#40;investigator&#41; study&#46; Patient&#39;s satisfaction outcome could have been influenced by participants unblinding&#46; A blinded investigator evaluated photodamage improvement but tolerability assessment was performed by an unblinded investigator&#46; All split-faces were included in the analysis and follow-ups were performed in all patients&#46; Patient&#39;s satisfaction through photographs evaluation was not specified in the methods section&#44; but was included in the abstract and in the discussion section of the manuscript&#46; Telangiectasia and erythema results were only depicted in the discussion section&#46; Sample size calculation was not specified&#46; The power of the study might have led to non-statistical significant differences in some outcomes at different time-points&#46; Fluence changes might have influenced the results&#46; Baseline characteristics of groups were not included&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">The method of sequence generation was not reported&#46; The method used for allocation concealment was not described&#46; Although the study was labeled as double-blind&#44; it was unclear who was also blinded besides the outcome assessors&#46; A blinded &#8220;independent&#8221; investigator evaluated outcomes but it was unclear if assessments were performed clinically or through the photographs taken&#46; Measures used to assure outcome assessor&#39;s blinding were not included in the article&#46; An ITT analysis was not performed&#46; Two patients withdrew from the study&#58; one due to an allergy to IPL&#44; but it was unclear which side of the face &#40;or whole face&#41; was affected&#46; In the other excluded patient&#44; it was unclear if not meeting study requirements was related to the type of intervention received&#46; The exclusion of these 2 patients in the analysis might have influenced the results due to the low power of the study&#46; Selective reporting was not detected&#46; This was an industry-sponsored trial with positive results&#44; with scarce specific data on potential conflicts of interest&#46; Sample size calculation was not specified&#46; Variations in IPL parameters according to individual features might have influenced final results&#46; Baseline characteristics of groups were not included&#46;</p>"
            ]
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              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">An ITT analysis was not performed&#46; Two patients withdrew from the study&#46; The exclusion of these 2 patients in the analysis might have influenced the results due to the low power of the study&#46;</p>"
            ]
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              "identificador" => "tblfn0020"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Sample size calculation was not specified&#46; The low power of the study might have led to non-statistical significant differences in outcomes when contralateral comparisons were made&#46;</p>"
            ]
            4 => array:3 [
              "identificador" => "tblfn0025"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0025">The risk in the intervention group &#40;and its 95&#37; confidence interval&#41; is based on the assumed risk in the comparison group and the relative effect of the intervention &#40;and its 95&#37; CI&#41;&#46; CI&#58; confidence interval&#59; RR&#58; risk ratio&#46;</p> <p class="elsevierStyleNotepara" id="npar0030">GRADE Working Group grades of evidence&#58;</p> <p class="elsevierStyleNotepara" id="npar0035">High quality&#58; we are very confident that the true effect lies close to that of the estimate of the effect&#46;</p> <p class="elsevierStyleNotepara" id="npar0040">Moderate quality&#58; we are moderately confident in the effect estimate&#58; the true effect is likely to be close to the estimate of the effect&#44; but there is a possibility that it is substantially different&#46;</p> <p class="elsevierStyleNotepara" id="npar0045">Low quality&#58; our confidence in the effect estimate is limited&#58; the true effect may be substantially different from the estimate of the effect&#46;</p> <p class="elsevierStyleNotepara" id="npar0050">Very low quality&#58; we have very little confidence in the effect estimate&#58; the true effect is likely to be substantially different from the estimate of effect&#46;</p>"
            ]
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">MAL for Facial Photodamage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient or population&#58; Facial Photodamage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Setting&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Intervention&#58; MAL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Comparison&#58; any intervention&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Outcomes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Anticipated absolute effects<a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">&#42;</span></a> &#40;95&#37; CI&#41;</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Relative effect &#40;95&#37; CI&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">No&#46; of participants &#40;studies&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Quality of the evidence &#40;GRADE&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Comments&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk with Any intervention&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk with MAL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Failure to achieve good cosmetics results&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">500 per 1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">100 per 1000 &#40;5&#8211;1000&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RR 0&#46;20 &#40;0&#46;01&#8211;3&#46;20&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8 &#40;1 study&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">a</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed&#44; a full recommendation cannot be made&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Failure to improve fine lines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">300 per 1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">99 per 1000 &#40;12&#8211;807&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RR 0&#46;33 &#40;0&#46;04&#8211;2&#46;69&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20 &#40;1 study&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">c</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed&#44; a full recommendation cannot be made&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Global Photodamage failure to improve&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">980 per 1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">39 per 1000 &#40;10&#8211;157&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RR 0&#46;04 &#40;0&#46;01&#8211;0&#46;16&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">98 &#40;1 study&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed&#44; a full recommendation cannot be made&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Global Photodamage failure to improve&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">900 per 1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">171 per 1000 &#40;72&#8211;378&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RR 0&#46;19 &#40;0&#46;08&#8211;0&#46;42&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">60 &#40;1 study&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed&#44; a full recommendation cannot be made&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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              "identificador" => "tblfn0030"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0055">The method of sequence generation was not reported&#46; The method used for allocation concealment was not described&#46; Measures used for blinding were not specified&#46; It was not clear if patients were blinded for satisfaction assessment&#46; Quote&#58; &#8220;A blinded investigator evaluated each side of the perioral area&#8221;&#46; All split-faces were included in the analysis&#46; Safety outcome was not specified in the methods section&#44; but was included in the analysis&#46; Only superficial wrinkles were evaluated but other photodamage features were not included&#46; Baseline characteristics of groups were not included&#46; Potential conflicts of interests and financial support were not described&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0035"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0060">Neither sample size calculation nor statistical tests used in analysis&#44; were specified&#46; The low power of the study might have led to non-statistical significant differences&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0040"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0065">The method of sequence generation was not reported&#46; The method used for allocation concealment was not described&#46; It was unclear if the study was single or double-blinded&#46; A blinded investigator evaluated photodamage improvement through baseline vs post-treatment patient&#39;s photographs but blinding of side effects assessment was not specified&#46; Measures used to assure outcome assessor&#39;s blinding were not described&#46; Nine out of ten patients completed follow-ups&#46; No intention to treat analysis &#40;ITT&#41; was specified&#46; Safety outcome was not specified in the methods section&#44; but was included in the results section of the manuscript&#46; Side-effects outcomes were measured as ordinal variables but in the analysis section these were treated statistically as quantitative variables&#46; A qualitative comparison of clinical facial photodamage improvement was performed from baseline vs post-treatment in the same split-face&#44; but there were neither contralateral comparisons&#44; nor statistical comparisons for this outcome&#46; Baseline characteristics of groups were not included&#46;</p>"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0070">Sample size calculation was not specified&#46; The lack of an ITT analysis could have an impact in efficacy results due to the small sample size of the study&#46; Similarly&#44; the low power of the study might have led to non-statistical significant differences in all outcomes&#46;</p>"
            ]
            4 => array:3 [
              "identificador" => "tblfn0050"
              "etiqueta" => "&#42;"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0075">The risk in the intervention group &#40;and its 95&#37; confidence interval&#41; is based on the assumed risk in the comparison group and the relative effect of the intervention &#40;and its 95&#37; CI&#41;&#46; CI&#58; confidence interval&#59; RR&#58; risk ratio&#46;</p> <p class="elsevierStyleNotepara" id="npar0080">GRADE Working Group grades of evidence&#58;</p> <p class="elsevierStyleNotepara" id="npar0085">High quality&#58; we are very confident that the true effect lies close to that of the estimate of the effect&#46;</p> <p class="elsevierStyleNotepara" id="npar0090">Moderate quality&#58; we are moderately confident in the effect estimate&#58; the true effect is likely to be close to the estimate of the effect&#44; but there is a possibility that it is substantially different&#46;</p> <p class="elsevierStyleNotepara" id="npar0095">Low quality&#58; our confidence in the effect estimate is limited&#58; the true effect may be substantially different from the estimate of the effect&#46;</p> <p class="elsevierStyleNotepara" id="npar0100">Very low quality&#58; we have very little confidence in the effect estimate&#58; the true effect is likely to be substantially different from the estimate of effect&#46;</p>"
            ]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0150" class="elsevierStyleSimplePara elsevierViewall">Summary of findings&#46;</p>"
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    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:55 [
            0 => array:3 [
              "identificador" => "bib0280"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mechanisms of photoaging and chronological skin aging"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46;J&#46; Fisher"
                            1 => "S&#46; Kang"
                            2 => "J&#46; Varani"
                            3 => "Z&#46; Bata-Csorgo"
                            4 => "Y&#46; Wan"
                            5 => "S&#46; Datta"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Dermatol"
                        "fecha" => "2002"
                        "volumen" => "138"
                        "paginaInicial" => "1462"
                        "paginaFinal" => "1470"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12437452"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0285"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "&#91;Skin aging&#93;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "E&#46; Kohl"
                            1 => "M&#46; Landthaler"
                            2 => "R&#46;M&#46; Szeimies"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00105-009-1790-5"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hautarzt"
                        "fecha" => "2009"
                        "volumen" => "60"
                        "paginaInicial" => "917"
                        "paginaFinal" => "933"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19898765"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0290"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Intrinsic skin aging&#58; the role of oxidative stress"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "B&#46; Polj&#353;ak"
                            1 => "R&#46;G&#46; Dahmane"
                            2 => "A&#46; Godi&#263;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Acta Dermatovenerol Alp Pannonica Adriat"
                        "fecha" => "2012"
                        "volumen" => "21"
                        "paginaInicial" => "33"
                        "paginaFinal" => "36"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23000938"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
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Review
Photodynamic Therapy Interventions in Facial Photodamage: A Systematic Review
Terapia fotodinámica en el fotodaño facial: revisión sistemática
G. Sanclementea,b,
Autor para correspondencia
, V. Ruiz-Cañasa, J.M. Mirandaa, A.P. Ferrína, P.A. Ramireza, G.N. Hernandeza
a Grupo de Investigación Dermatológica (GRID), Universidad de Antioquia, Medellín, Colombia
b IPS Universitaria, Universidad de Antioquia, Medellín, Colombia
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a down regulation of the transforming growth factor-b &#40;TGF-b&#41; type II receptor &#40;a major regulator of dermal extracellular matrix &#40;ECM&#41; synthesis&#41;&#44; and by a disturbed TGF-b activity that also stimulates fibroblast proliferation&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">7&#8211;10</span></a> Skin collagen is also affected by UV-induced matrix metalloproteinases &#40;MMP&#41;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">11</span></a> such as MMP-1 &#40;fibroblast collagenase&#41;&#44; MMP-9 &#40;gelatinase&#41; and MMP-3 &#40;stromelysin&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">10&#44;12</span></a> and solar elastosis seems to be a consequence of an increased production of elastic fibers and elastin degradation by MMP-12 &#40;human macrophage metalloelastase&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">10&#44;13&#8211;15</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Photodynamic therapy &#40;PDT&#41; is a selective therapeutic modality that combines an oxygen rich environment and a light source that stimulates a photosensitizing agent to produce singlet oxygen which is highly toxic to the cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">16&#44;17</span></a> Porphyrins and particularly hematoporphyrins &#40;e&#46;g&#46;&#58; photofrin&#41; were the first intravenous substances used for PDT&#44; characterized by their long-term accumulation in target tissue that required rigorous photoprotection for several weeks after administration&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">17</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In 1990 new topical porphyrins such as 5-aminolevulinic acid &#40;ALA&#41; or its methyl ester &#40;MAL&#41; emerged&#44; which could both easily penetrate the epidermis and produce short-term circumscribed photosensitivity&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">18</span></a> More recently&#44; hexylester 5-aminolevulinate &#40;HAL&#41; has been proposed to induce formation of high concentrations of PpIX in neoplastic tissue&#44; but its use is still experimental&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">19</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">These molecules intervene in heme biosynthesis intracellular pathway&#44; by inducing the formation of a photoactive porphyrin known as protoporphyrin IX &#40;PpIX&#41;&#44; which is an efficient photosensitizer that accumulates particularly in photodamaged skin&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">17</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">PDT requires either an incoherent&#47;coherent light source that should be ideally specific to the chromophore&#47;photosensitizer used&#46; Incoherent light devices include a continuous-wave red light &#40;635<span class="elsevierStyleHsp" style=""></span>nm&#41;&#44; blue light &#40;417<span class="elsevierStyleHsp" style=""></span>nm&#41; and intense-pulsed light &#40;IPL&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">20</span></a> whereas lasers are among the most used coherent light equipment&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">20</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">As photosensitizers can either localize in lysosomes&#44; mitochondria&#44; Golgi apparatus&#44; endoplasmic reticulum&#44; and plasma membranes&#44; PDT effects are a consequence of how PS interact with cells within the target tissue&#47;organ or tumor&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">21&#44;22</span></a> Moreover&#44; it seems that PDT direct DNA cellular damage can occur via modifications of guanine moiety and through strand breaks at uracil and thymine sites&#44; whereas indirect DNA disruption is explained by deactivation of repairing enzymes by free radicals and singlet oxygen production&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">23</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">In addition&#44; skin effects of topical PDT include solar elastosis improvement and neocollagenesis via the induction of expression of collagen type I&#47;III production&#44; MMP-1&#44;-3&#44;-9 and-12 down-regulation&#44; and TGF &#946; up-regulation&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">10&#44;24</span></a> Photodynamic therapy with MAL has also been reported to increase dermal thickness and to improve collagen&#44; elastic tissue and perifollicular fibrosis in treated skin&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">25&#44;26</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Several procedures have been used for actinic damage treatment &#40;e&#46;g&#46;&#58; chemical exfoliation&#44; topical retinoids&#44; lasers&#44; intense pulsed light &#40;IPL&#41; and LEDs &#40;light emitting diodes&#41;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">24&#44;27&#8211;34</span></a> However&#44; and according to a systematic review&#44; there is limited scientific evidence to support the preferential use of any of these therapies in photodamaged skin&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">35</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Up to know&#44; topical PDT use in the treatment of photodamage is still off-label&#46; Therefore&#44; as uncertainty still remains in this field&#44; this paper aims to assess published scientific evidence to establish the efficacy and safety of such therapy&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Search strategies</span><p id="par0055" class="elsevierStylePara elsevierViewall">We aimed to identify all relevant published or unpublished RCTs regardless of language&#46; Searches were performed during the last 10 years&#44; and updated up to 4 May 2016&#46; Search terms with results are depicted in Supplementary Material 1&#46; Trial registries were scanned up to December 15&#44; 2015&#44; using the search terms&#58; &#8220;photodamage&#8221;&#44; &#8220;photoaging&#8221;&#44; &#8220;photodynamic therapy&#8221; and &#8220;photodynamic rejuvenation&#8221; &#40;Supplementary Material 2&#41;&#46; We also checked for relevant references in included and excluded studies&#46; If full text of the articles was not available&#44; we tried to contact authors&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">We did not perform a separate search for adverse effects of the specified intervention&#46; However&#44; we examined data on adverse effects from all included studies&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Inclusion criteria</span><p id="par0065" class="elsevierStylePara elsevierViewall">All parallel randomized controlled trials &#40;RCTs&#41; of PDT for facial photodamage &#40;dermatoheliosis&#41;&#47;photoaging and&#47;or photodynamic rejuvenation that included adult participants diagnosed with facial photodamage &#40;dermatoheliosis&#41; or photoaging&#44; and who have been treated with any PDT-based rejuvenation procedure&#44; were included&#46; Any photodynamic-based intervention for photodamage &#40;dermatoheliosis&#41; or photoaging was considered&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Types of outcomes measures</span><p id="par0070" class="elsevierStylePara elsevierViewall">Primary endpoints included&#58; &#40;1&#41; the proportion of participants who had an improvement&#47;failure in global facial photodamage&#59; &#40;2&#41; quality of life &#40;QoL&#41; changes measured through any validated and recognized generic or disease-specific instrument&#59; &#40;3&#41; any adverse events&#44; safety and tolerability&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Secondary outcomes corresponded to&#58; &#40;1&#41; the proportion of participants who had an improvement&#47;failure in facial hyperpigmentation&#44; wrinkles&#44; sallowness&#44; erythema or roughness according to a validated and&#47;or recognized generic or disease-specific instrument&#59; &#40;2&#41; change in facial cosmetic appearance&#59; &#40;3&#41; participant satisfaction&#59; &#40;4&#41; pain evaluation after the photodynamic-based procedure&#44; and &#40;5&#41; cost effectiveness studies&#44; if available&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Data extraction and synthesis</span><p id="par0080" class="elsevierStylePara elsevierViewall">Four authors &#40;V&#46;R&#46;&#44; J&#46;M&#46;&#44; A-P F&#46;&#44; G&#46; S&#46;&#41; checked the searched titles and abstracts&#46; Potentially relevant studies were selected for full-text review&#46; All authors independently assessed whether each study met the predefined selection criteria&#44; and differences were resolved by discussion&#46; The same four authors performed data extraction in pre-established data collection formats and independently assessed the risk of bias of included studies as low&#44; high or unclear according to a domain-based evaluation described in the <span class="elsevierStyleItalic">Cochrane Handbook for Systematic Reviews of Interventions</span><a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">36</span></a> &#40;e&#46;g&#46;&#58; &#8216;sequence generation&#8217;&#59; &#8216;allocation concealment&#8217;&#59; &#8216;blinding&#8217;&#59; &#8216;outcome data&#8217;&#59; &#8216;selective reporting&#8217; and other sources of bias&#41; that could put it at high risk of bias &#40;e&#46;g&#46; baseline imbalance&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Statistical issues</span><p id="par0085" class="elsevierStylePara elsevierViewall">We planned to include only parallel designed trials&#46; Dichotomous outcomes data were presented as reported in each individual study&#46; However&#44; if sufficient data were available&#44; outcomes data were presented as relative risks &#40;RR&#41; with their associated 95&#37; confidence intervals &#40;CIs&#41; and analyzed them in the Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#44; using the Mantel&#8211;Haenszel test&#44; unless we stated otherwise&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">We re-analyzed the data originally described according to an intention to treat &#40;ITT&#41; principle&#44; whenever possible&#46; If study authors conducted a per-protocol analysis&#44; we evaluated potential imbalances in the dropout rate between the trial arms to determine bias&#46; If treatment by allocation population was unavailable&#44; we used an available case population and reported this accordingly&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">We planned to evaluate clinical&#44; statistical&#44; and methodological heterogeneity&#46; Statistical heterogeneity was planned to be tested by using the <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span> statistic&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">36</span></a> If substantial heterogeneity &#40;<span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span> greater than 60&#37;&#41; was found for the primary outcomes&#44; we planned to explore reasons for heterogeneity&#46; As at least ten studies suitable for meta-analysis were needed for funnel plot asymmetry testing&#44;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">37</span></a> we were unable to perform such test&#46; Also&#44; as we were unable to identify an adequate number of homogenous studies &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>3&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">38</span></a> we did not perform a meta-analysis but we summarized the data for each trial qualitatively&#46; The number of studies was also inadequate to perform subgroup and sensitivity analysis&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Studies description</span><p id="par0100" class="elsevierStylePara elsevierViewall">After removal of duplicates our searches retrieved 1293 references&#46; Further to titles and abstracts examination&#44; we excluded 1235 references from the review&#46; We obtained full-text copies of the remaining 51 records for further evaluation&#44; and after evaluation&#44; 39 studies were excluded&#46; Reasons for their exclusion are depicted in Supplementary Material 3&#46; Exclusions were made only after assessment of the full-text reports&#46; The most frequent reason for exclusion was that they were non-RCTs&#46; Regarding ongoing studies&#44; we only identified one ongoing study&#44; which is in the recruiting phase &#40;Supplementary Material 3&#41;&#46; Re-analysis of retrieved data was not necessary&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">All retrieved studies were published in English&#46; Thirteen references to 12 studies were finally included&#44; as one same trial had two reports<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">25&#44;39</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; A total of 286 participants &#40;135 patients from ALA studies and 151 from MAL studies&#41; were evaluated&#46; Among these&#44; 30 were men and 212 women&#44; but in 2 studies&#44; gender of participants was not specified<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;40</span></a> &#40;Supplementary Material 4&#41;&#46; The age of the participants ranged from 35 to 82 years&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">Among all 12 included randomized trials&#44; 6 studies used ALA and 6 MAL&#44; as chromophores&#46; Only 2 studies used a placebo as control<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41</span></a> and 10 had an active control treatment arm&#46; Studies were published from year 2004 until 2015&#46; Four studies were conducted in the USA&#44;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;42&#8211;44</span></a> four in South America&#44;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#8211;41&#44;45</span></a> 2 in Spain&#44;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">27&#44;46</span></a> 1 in Denmark&#44;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">47</span></a> and one in China&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">48</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">The range number of participants included in the individual studies varied from 4 to 60 participants&#46; Ten studies had a split-face design whereas 2 had a full-face design&#46; All patients were diagnosed with mild to severe facial photodamage&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The included studies evaluated the following interventions&#58; &#40;1&#41; IPL vs IPL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>5-ALA in a split-face design<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;44&#44;48</span></a>&#59; &#40;2&#41; laser fractional resurfacing alone vs laser fractional resurfacing<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light in a split-face design<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">46</span></a>&#59; &#40;3&#41; MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light with 1<span class="elsevierStyleHsp" style=""></span>h incubation vs MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light with 3<span class="elsevierStyleHsp" style=""></span>h incubation in a split-face design<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">27</span></a>&#59; &#40;4&#41; IPL waveband from 530 to 750<span class="elsevierStyleHsp" style=""></span>nm and short pulse durations &#40;J&#47;cm<span class="elsevierStyleSup">2</span>&#44; 2&#8211;2&#46;5<span class="elsevierStyleHsp" style=""></span>ms&#44; delay 10<span class="elsevierStyleHsp" style=""></span>ms&#41;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>0&#46;5&#37; liposome encapsulated vs IPL &#40;waveband from 400 to 720<span class="elsevierStyleHsp" style=""></span>nm&#41;&#44; three passes were performed &#40;3&#46;5<span class="elsevierStyleHsp" style=""></span>J&#47;cm<span class="elsevierStyleSup">2</span>&#44; 30<span class="elsevierStyleHsp" style=""></span>ms pulse duration&#41;&#44; also in a split-face design<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">47</span></a>&#59; &#40;5&#41; blue light at different incubation times<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>5-ALA in a split-face design<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">42</span></a>&#59; &#40;6&#41; IPL vs IPL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>5-ALA in a full-face design<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">40</span></a>&#59; &#40;7&#41; MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light with 3<span class="elsevierStyleHsp" style=""></span>h incubation vs placebo<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light with 3<span class="elsevierStyleHsp" style=""></span>h incubation in a split-face design<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">39</span></a>&#59; &#40;8&#41; MAL with 1<span class="elsevierStyleHsp" style=""></span>h incubation<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light vs MAL with 1<span class="elsevierStyleHsp" style=""></span>h incubation<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>blue light in a split-face design<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">43</span></a>&#59; &#40;9&#41; MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light vs MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1&#46;5<span class="elsevierStyleHsp" style=""></span>mm length micro-needling in a split-face design<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">45</span></a>&#59; and &#40;10&#41; MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>h daylight exposure vs placebo<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>h daylight exposure in a full-face design&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">41</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The majority of included studies &#40;except two<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41</span></a>&#41; did not specify primary and secondary outcomes&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Facial photodamage assessment was performed by the use of several original or modified scales such the Griffith&#39;s&#44; Dover&#39;s&#44; Fitzpatrick&#39;s&#44; or arbitrary scales&#46; Four studies reported that they had applied a &#8220;modified version&#8221; of another previous developed scale&#44;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41&#44;45&#44;48</span></a> but authors did not provide details of how and if their &#8220;modified version&#8221; was tested prior to its use&#46; Only one study assessed intervention&#39;s effects on quality of life &#40;QoL&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">41</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">A large proportion of the trials &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#41; assessed intervention-associated adverse events <span class="elsevierStyleItalic">a priori</span>&#44; either through questionnaires that rated the treatment tolerability&#44; or as skin reactions&#44; such as erythema&#44; dryness&#44; edema&#44; oozing&#44; vesiculation&#44; crusting&#44; pigmentation disturbances&#44; skin atrophy&#44; scarring and desquamation or scaling&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">28</span></a> In addition&#44; several included studies assessed secondary outcomes&#44; but overall&#44; the methods used for measurement and the timing of the assessments were not uniform or clear&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Risk of bias Assessment</span><p id="par0140" class="elsevierStylePara elsevierViewall">Risk of bias for each included study and graphs are depicted in Supplementary Material 4&#44; and <a class="elsevierStyleCrossRefs" href="#fig0010">Figs&#46; 2 and 3</a>&#44; respectively&#46; As one of the reviewers &#40;GS&#41; was the main author of 2 studies&#44; both studies were assessed only by the other 3 assessors&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0145" class="elsevierStylePara elsevierViewall">We assessed the global risk of bias for each included study&#44; and we considered two studies to be at &#8220;low risk of bias&#8221; as both met all criteria across all domains in the Cochrane &#8220;Risk of bias&#8221; assessment tool &#40;plausible bias unlikely to seriously alter the results&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41</span></a> We rated the remaining 10 studies as at &#8220;unclear risk of bias&#8221; &#40;plausible bias that raises some doubt about the result&#41; because one or more criteria were assessed as unclear &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">An important number of included studies &#40;9&#41; provided insufficient detail to enable us to make accurate judgements in respect to the domain &#8220;concealment of the allocation sequence&#8221;&#46;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">27&#44;28&#44;40&#44;42&#8211;44&#44;46&#8211;48</span></a> Indeed&#44; intervention allocations masking through sequentially numbered&#44; opaque&#44; sealed envelopes or pharmacy-controlled allocation was only performed in 2 studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41</span></a> Similarly&#44; the &#8220;blinding of outcome assessors&#8221; domain was unclear in 5 studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">27&#44;40&#44;42&#44;47&#44;48</span></a> and only two studies described blinding of study participants and personnel in sufficient detail&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41</span></a> Also&#44; baseline characteristics of patients or groups were only described in 3 studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41&#44;43</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">Incomplete data of patients lost to follow-up&#44; and subsequent per-protocol analyses were other important sources of potential bias in a number of the included studies&#46; In addition&#44; trial protocol was provided in only two studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41</span></a> Judgements were amended as required&#44; after contact with trial investigator&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">45</span></a> In some other studies authors replied that they no longer had information regarding trial methods<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">42</span></a> and for other studies&#44; we did not obtain a reply from authors&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Effects of interventions</span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">5-ALA</span><p id="par0160" class="elsevierStylePara elsevierViewall">Although 6 studies evaluated the effect of 5-ALA as chromophore&#44; either insufficient data or just baseline vs post-treatment comparisons limited relative risks calculations which could be performed only for 3 studies<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;47&#44;48</span></a> &#40;<a class="elsevierStyleCrossRefs" href="#fig0020">Figs&#46; 4&#8211;6</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="fig0030"></elsevierMultimedia><p id="par0165" class="elsevierStylePara elsevierViewall">In general&#44; there was a tendency to less treatment failure in ALA-treated split-faces&#46; Also&#44; we were unable to determine primary and secondary endpoints in all 5-ALA studies&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">The effect of ALA in actinic keratosis&#44; as well as in facial photodamage was assessed in 2 studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">40&#44;42</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Investigator assessment of changes in facial photodamage and participant&#39;s photodamage evaluation were performed through digital standardized photographs in 3 studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">40&#44;44&#44;47</span></a> and two studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;48</span></a> respectively&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Partial or full sponsoring of ALA trials by the pharmaceutical industry was detected in 4 studies<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;40&#44;42&#44;48</span></a> and in 2 studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">44&#44;47</span></a> sponsoring information was lacking&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Photodamage results according to the timeline at which outcomes were assessed in ALA studies varied from 1 month after last session<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;42</span></a>&#44; 2 months after last session&#44;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">40</span></a> 1&#8211;2 months after last session&#44;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">48</span></a> 3 months after last session&#44;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">47</span></a> and at 1&#44; 3 and 6 months&#44; after last session&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">44</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">Regarding patient related outcomes&#44; subject satisfaction was evaluated in 4 out of 6 ALA studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;42&#44;47&#44;48</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">In general&#44; more erythema&#44; edema and desquamation were reported in the ALA-treated side of the face&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">5-ALA-related adverse events</span><p id="par0200" class="elsevierStylePara elsevierViewall">Herpes simplex reactivation and post-inflammatory hyperpigmentation were reported in Touma et al&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">42</span></a> and in Xi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">48</span></a> studies&#44; respectively&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">A summary of findings table of 5-ALA results according to GRADE standards is depicted in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">MAL</span><p id="par0210" class="elsevierStylePara elsevierViewall">Although 6 studies evaluated the effect of MAL as chromophore&#44; the lack of contralateral comparisons or insufficient data allowed the calculation of relative risks only for 4 out of 6 studies &#40;<a class="elsevierStyleCrossRefs" href="#fig0050">Figs&#46; 7&#8211;10</a>&#41;&#46;</p><elsevierMultimedia ident="fig0050"></elsevierMultimedia><elsevierMultimedia ident="fig0035"></elsevierMultimedia><elsevierMultimedia ident="fig0040"></elsevierMultimedia><elsevierMultimedia ident="fig0055"></elsevierMultimedia><p id="par0215" class="elsevierStylePara elsevierViewall">We also were unable to differentiate primary and secondary endpoints in 4 out of 6 studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">27&#44;43&#44;45&#44;46</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">The effect of MAL&#44; actinic keratosis&#44; and in facial photodamage simultaneously was assessed in 2 studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">43&#44;45</span></a> Investigator assessment of photodamage outcomes was performed through digital standardized photographs in 1 study&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">43</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">In general&#44; timelines for photodamage outcome evaluation in MAL trials ranged from 1 to 3 months after last session&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">Partial or full sponsoring of trials by the pharmaceutical industry was detected in 3 studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41&#44;43</span></a> Sponsoring details were not described in 2 studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">27&#44;46</span></a> and one study was developed without any sponsor&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">45</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">In respect to patient satisfaction&#44; such outcome was evaluated in 3 studies with better satisfaction scores in the MAL treated split-face&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;43&#44;46</span></a> In addition&#44; just 1 out of the 12 studies &#40;ALA and MAL&#41; included a quality of life outcome&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">41</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">Overall&#44; erythema&#44; edema and desquamation were more frequently reported in the side of the face that included MAL as chromophore in all studies&#44; except in one study<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">43</span></a> in which no statistical differences between the use of blue vs red light were found&#44; but also mild discomfort was more frequent with red-light exposure&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">MAL-related adverse events</span><p id="par0245" class="elsevierStylePara elsevierViewall">Herpes simplex reactivation was reported in two studies whereas post-inflammatory hyperpigmentation was described in 3 studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41&#44;46</span></a> A severe infection related to the concomitant use of microdermabrasion<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PDT was reported in 1 out of 10 patients in Torezan et al&#46;&#8217;s<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">45</span></a> study and a severe allergic reaction not related to PDT was reported in another study&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">39</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">A summary of findings table of MAL results according to GRADE standards is depicted in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Discussion</span><p id="par0255" class="elsevierStylePara elsevierViewall">To the best of our knowledge&#44; this is the first published systematic review &#40;SR&#41; to assess and examine the evidence for the efficacy and safety of PDT in facial photodamage&#44; and although the full protocol of this SR was not published &#40;just its abstract&#41;&#44; it is available upon request to correspondence author&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">Two high quality studies suggest that MAL-PDT is effective in the treatment of facial photodamage&#44; but low to moderate quality of evidence shows that PDT with ALA seems to be also effective&#46; Although adverse events &#40;AEs&#41; were reported inadequately in most studies&#44; non-serious reported AEs include herpes simplex recurrence and post-inflammatory hyperpigmentation&#44; particularly in studies that included participants with darker skin &#40;3 out of 4 studies with PIH reports&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41&#44;46&#44;48</span></a></p><p id="par0265" class="elsevierStylePara elsevierViewall">The main objectives of a randomized clinical trial are to assess efficacy and safety of an intervention&#46; In this respect&#44; concealment and blinding are key domains in the assessment of risk of bias&#46;<a class="elsevierStyleCrossRefs" href="#bib0520"><span class="elsevierStyleSup">49&#8211;51</span></a> In particular&#44; the methods used to generate the allocation sequence and how the sequence was concealed&#44; are the most important and sensitive indicators that bias has been minimized in a clinical trial&#44; as participants and investigators are masked to the upcoming assignment&#44; and therefore could not &#8220;manipulate&#8221; it&#46; Also&#44; standardization of outcomes and objective measurement are key elements not only for clinical decision making&#44; but also to establish health policies&#46;<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">52&#8211;54</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">Overall&#44; the evidence provided by this review was limited mainly due to outcome inconsistencies&#44; the lack of description of randomization methods&#47;sequence generation&#44; and a lack of a double-blind trial design&#46; Moreover&#44; the high heterogeneity of studies did not allow a quantitative synthesis of the evidence found&#46; However&#44; there was a tendency for having a better result when PDT with any chromophore was used&#44; when compared to the use of a light source alone&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">Most of the included studies in this review were performed before the requirement of trial registration&#46; As a result of insufficient data and the lack of reporting&#44; we were &#8220;forced&#8221; to downgrade the quality of evidence to &#8220;unclear risk of bias&#8221;&#44; as we appraised these studies according to the information contained within the full text of each article&#46; However&#44; more unbiased judgment elements could have been obtained if we were able to get a reply from all authors&#44; but such information could only be gathered from one main author&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall">In this review&#44; it is unlikely that we have missed studies with an important sample size as we performed a rigorous systematic search of published and unpublished literature and we also tried to contact leading experts&#46; Nonetheless&#44; we cannot absolutely rule out the influence of publication bias&#46; Unfortunately we were unable to reliably assess the presence of publication bias&#44; given the small number of included studies&#46; Also&#44; we attempted to lower potential biases in the evaluation of two MAL trials<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41</span></a> performed by one of the reviewers of this systematic review by limiting their assessment only by the other 3 assessors&#46;</p><p id="par0285" class="elsevierStylePara elsevierViewall">The applicability of evidence found by this review corresponds to what is usual in clinical practice&#44;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">4&#44;55</span></a> as included trials covered the usual age spectrum of participants who seek a dermatologist for photodamage therapeutic options&#46; However&#44; it is important to bear in mind that depending on the severity of facial photodamage&#44; patients over 70 years old might not be the best candidates for PDT as they often require more invasive procedures such as resurfacing with ablational lasers and&#47;or surgery&#46; Also&#44; as all included studies had participants with Fitzpatrick&#39;s SPT from I through IV&#44; the applicability of the evidence in SPT V-VI is limited&#46; Similarly&#44; results applicability in men could be affected&#44; as the majority of included participants&#44; were women&#46;</p><p id="par0290" class="elsevierStylePara elsevierViewall">In conclusion&#44; the findings in our review showed that MAL PDT was effective for the treatment of facial photodamage&#44; but also have highlighted that only a small number of published trials have followed the Consolidated Standards of Reporting Trials &#40;CONSORT-Statement&#41; and the criteria of evidence-based medicine&#46; Such standards are necessary to heighten evidence strength and quality in future trials design&#46; Also&#44; as there is a relative paucity of long-term evaluations of the effect of PDT in facial photodamage and in quality of life&#44; such knowledge gaps deserve further research&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Sponsoring</span><p id="par0295" class="elsevierStylePara elsevierViewall">This work was supported by the Group of Investigative Dermatology-GRID of the <span class="elsevierStyleGrantSponsor" id="gs1">Universidad de Antioquia</span>&#44; Medellin&#44; Colombia and by the <span class="elsevierStyleGrantSponsor" id="gs2">Fundacion Dermabase</span>&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Conflict of interest</span><p id="par0300" class="elsevierStylePara elsevierViewall">Dr&#46; Gloria Sanclemente has participated in advisory boards and has received honoraria and scientific meeting support from Galderma Laboratories&#46;</p><p id="par0305" class="elsevierStylePara elsevierViewall">Dr&#46; Veronica Ruiz Ca&#241;as has received scientific meeting support from Galderma Laboratories&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall">Dr&#46; Jenny Marcela Miranda Orozco has received scientific meeting support from Galderma Laboratories&#46;</p><p id="par0315" class="elsevierStylePara elsevierViewall">Dr&#46; Alba Patricia Ferr&#237;n Bastidas has received scientific meeting support from Galderma Laboratories&#46;</p><p id="par0320" class="elsevierStylePara elsevierViewall">Paola Andrea Ramirez has nothing to disclose</p><p id="par0325" class="elsevierStylePara elsevierViewall">Gilma Hernandez has nothing to disclose&#46;</p></span></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Photodynamic therapy &#40;PDT&#41; involves the combination of a light source and a photosensitizing agent to induce tissue damage via the generation of singlet oxygen&#46; Although topical PDT has been approved for other indications&#44; its use in facial photodamage is uncertain&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Aims</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">To assess the efficacy and safety of PDT in facial skin photoaging&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Methods</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">All randomized clinical trials &#40;RCTs&#41; evaluating the efficacy and safety of any form of topical PDT for the treatment of facial photodamage &#40;dermatoheliosis&#41; or photoaging in patients older than 18 years&#44; were included&#46; Photodynamic-therapy using any topical photosensitizing agent at any dose&#44; and with any light-source&#44; were considered&#46; Comparators were chemical exfoliation&#44; intense pulsed light &#40;IPL&#41;&#44; light emitting diodes &#40;LED&#41;&#44; dermabrasion or microdermabrasion&#44; ablative or non-ablative lasers&#44; injectables&#44; surgery&#44; placebo and&#47;or no treatment&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">A systematic search in PubMed&#44; Embase&#44; Lilacs&#44; Google Scholar and RCT&#39;s registry databases&#44; was performed&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Results</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Search was conducted up to May 4th 2016&#46; Four authors independently selected and assessed methodological quality of each RCT&#46; According to inclusion criteria&#44; twelve studies were included &#40;6 aminolevulinate &#40;ALA&#41; trials and 6 methyl aminolevulinate &#40;MAL&#41; trials&#41;&#44; but the majority of them had methodological constraints particularly in randomization description and patients&#47;outcome assessors blindness&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Discussion and conclusions</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Overall results indicated that PDT either with ALA or with MAL was effective and safe for facial photodamage treatment&#44; but high quality of evidence was found mainly for MAL studies&#46;</p></span>"
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        "resumen" => "<span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Introducci&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La terapia fotodin&#225;mica &#40;TF&#41; incluye una combinaci&#243;n de una fuente de luz y un agente fotosensibilizante para inducir da&#241;o tisular a trav&#233;s de la generaci&#243;n de ox&#237;geno singlete&#46; Aunque la TF se ha aprobado para otras indicaciones&#44; su uso en el fotoda&#241;o facial resulta incierto&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Objetivo</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Valorar la eficacia y seguridad de la TF en el fotoenvejecimiento de la piel del rostro&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">M&#233;todos</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Se incluyeron todos los ensayos cl&#237;nicos aleatorizados &#40;ECA&#41; que eval&#250;an la eficacia y seguridad de cualquier forma de TF t&#243;pica para el tratamiento del fotoda&#241;o facial &#40;dermatoheliosis&#41; o fotoenvejecimiento en pacientes mayores de 18 a&#241;os&#46; Se consider&#243; la TF que utiliza cualquier dosis de agente fotosensibilizante&#44; as&#237; como cualquier fuente lum&#237;nica&#46; Los comparadores fueron&#58; exfoliaci&#243;n qu&#237;mica&#44; luz pulsada intensa &#40;IPL&#41;&#44; diodo emisor de luz &#40;LED&#41;&#44; dermoabrasi&#243;n o microdermoabrasi&#243;n&#44; l&#225;seres ablativos o no ablativos&#44; inyectables&#44; cirug&#237;a&#44; placebo y&#47;o ausencia de tratamiento&#46;</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Se llev&#243; a cabo una b&#250;squeda sistem&#225;tica en las bases de datos de los registros de PubMed&#44; Embase&#44; Lilacs&#44; Google Scholar y ECA&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Resultados</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">La b&#250;squeda se realiz&#243; hasta el mes de mayo de 2016&#46; Cuatro autores seleccionaron y valoraron de manera independiente la calidad metodol&#243;gica de cada ECA&#46; Con arreglo a los criterios de inclusi&#243;n&#44; se incluyeron 12 estudios &#40;6 ensayos sobre aminolevulinato &#91;ALA&#93; y 6 sobre metiloaminolevulinato &#91;MAL&#93;&#41;&#44; aunque la mayor&#237;a de ellos conten&#237;an limitaciones metodol&#243;gicas&#44; particularmente en cuanto a la descripci&#243;n de la aleatorizaci&#243;n y la valoraci&#243;n a ciegas de los asesores de los pacientes&#47;resultados&#46;</p></span> <span id="abst0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Discusi&#243;n y conclusiones</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Los resultados generales indicaron que la TF&#44; tanto con ALA como con MAL&#44; era una terapia efectiva y segura para el tratamiento del fotoda&#241;o facial&#44; aunque se encontr&#243; evidencia de alta calidad principalmente en los estudios realizados sobre MAL&#46;</p></span>"
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            "Tamanyo" => 247778
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Risk of bias summary graph&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "fig0020"
        "etiqueta" => "Figure 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr4.jpeg"
            "Alto" => 391
            "Ancho" => 2336
            "Tamanyo" => 104738
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Forest plot of comparison&#58; 5-ALA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>IPL vs IPL alone&#44; outcome&#58; Global Photodamage failure to improve with <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20 subjects &#40;40 split-faces&#41;&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "fig0025"
        "etiqueta" => "Figure 5"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr5.jpeg"
            "Alto" => 424
            "Ancho" => 2336
            "Tamanyo" => 104978
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">5-ALA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>IPL vs IPL alone&#44; outcome&#58; 3&#46;1 Failure to improve according to a global score of photoaging &#40;analysis was performed with <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>26 patients &#40;52 splitfaces&#41;&#41;&#46; The 2 patients that were excluded were labeled as not improved in the 5-ALA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>IPL intervention group&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "fig0030"
        "etiqueta" => "Figure 6"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr6.jpeg"
            "Alto" => 379
            "Ancho" => 2336
            "Tamanyo" => 109979
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Forest plot of comparison&#58; liposome encapsulated 5-ALA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>IPL vs IPL alone&#44; outcome&#58; 5&#46;1 Failure to improve periorbital wrinkles&#46; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>37 subjects &#40;74 splitfaces&#41;&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
        ]
      ]
      6 => array:7 [
        "identificador" => "fig0050"
        "etiqueta" => "Figure 7"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr7.jpeg"
            "Alto" => 385
            "Ancho" => 2336
            "Tamanyo" => 102723
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">Forest plot of comparison&#58; MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>fractional laser vs fractional laser&#44; outcome&#58; 2&#46;1 Failure to achieve good cosmetics results&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
        ]
      ]
      7 => array:7 [
        "identificador" => "fig0035"
        "etiqueta" => "Figure 8"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr8.jpeg"
            "Alto" => 340
            "Ancho" => 2336
            "Tamanyo" => 111530
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">Forest plot of comparison&#58; 3<span class="elsevierStyleHsp" style=""></span>h MAL incubation<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light vs 1<span class="elsevierStyleHsp" style=""></span>h MAL incubation<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light&#44; outcome&#58; 4&#46;1 Failure to improve fine lines&#46; The excluded patient was labeled as a failure in the 1<span class="elsevierStyleHsp" style=""></span>h MAL incubation group&#46; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10 subjects &#40;20 split-faces&#41;&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
        ]
      ]
      8 => array:7 [
        "identificador" => "fig0040"
        "etiqueta" => "Figure 9"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr9.jpeg"
            "Alto" => 375
            "Ancho" => 2336
            "Tamanyo" => 112391
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">Forest plot of comparison&#58; 6 MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light vs placebo<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light&#44; outcome&#58; 6&#46;1 Global Photodamage failure to improve&#46; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>98 split-faces&#46; The subject who discontinued treatment due to an adverse reaction was labeled as a failure in the MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light group&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
        ]
      ]
      9 => array:7 [
        "identificador" => "fig0055"
        "etiqueta" => "Figure 10"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr10.jpeg"
            "Alto" => 366
            "Ancho" => 2336
            "Tamanyo" => 114460
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">Forest plot of comparison&#58; MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>daylight vs Placebo<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>daylight&#44; outcome&#58; 7&#46;1 Global Photodamage failure to improve&#46; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>60 subjects &#40;60 whole faces&#41;&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Center&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
        ]
      ]
      10 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
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            "identificador" => "at1"
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        "tabla" => array:2 [
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              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">5-ALA for facial photodamage&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient or population&#58; Facial Photodamage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Setting&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Intervention&#58; 5-ALA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Comparison&#58; Any intervention&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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            1 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Outcomes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Anticipated absolute effects<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">&#42;</span></a> &#40;95&#37; CI&#41;</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Relative effect &#40;95&#37; CI&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">No&#46; of participants &#40;studies&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Quality of the evidence &#40;GRADE&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Comments&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk with any intervention&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk with 5-ALA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Failure to improve according to a Global Photodamage scale&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">550 per 1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">198 per 1000 &#40;77&#8211;523&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RR 0&#46;36 &#40;0&#46;14&#8211;0&#46;95&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">40 &#40;1 RCT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed&#44; a full recommendation cannot be made&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Failure to improve according to a global score of photoaging&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">154 per 1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">115 per 1000 &#40;29&#8211;466&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RR 0&#46;75 &#40;0&#46;19&#8211;3&#46;03&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">52 &#40;1 RCT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed&#44; a full recommendation cannot be made&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Failure to improve periorbital wrinkles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">378 per 1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">299 per 1000 &#40;155&#8211;568&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RR 0&#46;79 &#40;0&#46;41&#8211;1&#46;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">74 &#40;1 RCT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed&#44; a full recommendation cannot be made&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1712289.png"
              ]
            ]
          ]
          "notaPie" => array:5 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">The method of sequence generation was not reported&#46; The method used for allocation concealment was not described&#46; It was a single-blinded &#40;investigator&#41; study&#46; Patient&#39;s satisfaction outcome could have been influenced by participants unblinding&#46; A blinded investigator evaluated photodamage improvement but tolerability assessment was performed by an unblinded investigator&#46; All split-faces were included in the analysis and follow-ups were performed in all patients&#46; Patient&#39;s satisfaction through photographs evaluation was not specified in the methods section&#44; but was included in the abstract and in the discussion section of the manuscript&#46; Telangiectasia and erythema results were only depicted in the discussion section&#46; Sample size calculation was not specified&#46; The power of the study might have led to non-statistical significant differences in some outcomes at different time-points&#46; Fluence changes might have influenced the results&#46; Baseline characteristics of groups were not included&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">The method of sequence generation was not reported&#46; The method used for allocation concealment was not described&#46; Although the study was labeled as double-blind&#44; it was unclear who was also blinded besides the outcome assessors&#46; A blinded &#8220;independent&#8221; investigator evaluated outcomes but it was unclear if assessments were performed clinically or through the photographs taken&#46; Measures used to assure outcome assessor&#39;s blinding were not included in the article&#46; An ITT analysis was not performed&#46; Two patients withdrew from the study&#58; one due to an allergy to IPL&#44; but it was unclear which side of the face &#40;or whole face&#41; was affected&#46; In the other excluded patient&#44; it was unclear if not meeting study requirements was related to the type of intervention received&#46; The exclusion of these 2 patients in the analysis might have influenced the results due to the low power of the study&#46; Selective reporting was not detected&#46; This was an industry-sponsored trial with positive results&#44; with scarce specific data on potential conflicts of interest&#46; Sample size calculation was not specified&#46; Variations in IPL parameters according to individual features might have influenced final results&#46; Baseline characteristics of groups were not included&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">An ITT analysis was not performed&#46; Two patients withdrew from the study&#46; The exclusion of these 2 patients in the analysis might have influenced the results due to the low power of the study&#46;</p>"
            ]
            3 => array:3 [
              "identificador" => "tblfn0020"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Sample size calculation was not specified&#46; The low power of the study might have led to non-statistical significant differences in outcomes when contralateral comparisons were made&#46;</p>"
            ]
            4 => array:3 [
              "identificador" => "tblfn0025"
              "etiqueta" => "&#42;"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0025">The risk in the intervention group &#40;and its 95&#37; confidence interval&#41; is based on the assumed risk in the comparison group and the relative effect of the intervention &#40;and its 95&#37; CI&#41;&#46; CI&#58; confidence interval&#59; RR&#58; risk ratio&#46;</p> <p class="elsevierStyleNotepara" id="npar0030">GRADE Working Group grades of evidence&#58;</p> <p class="elsevierStyleNotepara" id="npar0035">High quality&#58; we are very confident that the true effect lies close to that of the estimate of the effect&#46;</p> <p class="elsevierStyleNotepara" id="npar0040">Moderate quality&#58; we are moderately confident in the effect estimate&#58; the true effect is likely to be close to the estimate of the effect&#44; but there is a possibility that it is substantially different&#46;</p> <p class="elsevierStyleNotepara" id="npar0045">Low quality&#58; our confidence in the effect estimate is limited&#58; the true effect may be substantially different from the estimate of the effect&#46;</p> <p class="elsevierStyleNotepara" id="npar0050">Very low quality&#58; we have very little confidence in the effect estimate&#58; the true effect is likely to be substantially different from the estimate of effect&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0120" class="elsevierStyleSimplePara elsevierViewall">Summary of findings&#46;</p>"
        ]
      ]
      11 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Table "
            "rol" => "short"
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        ]
        "tabla" => array:2 [
          "tablatextoimagen" => array:2 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">MAL for Facial Photodamage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient or population&#58; Facial Photodamage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Setting&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Intervention&#58; MAL&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Anticipated absolute effects<a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">&#42;</span></a> &#40;95&#37; CI&#41;</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Relative effect &#40;95&#37; CI&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Quality of the evidence &#40;GRADE&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Comments&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk with Any intervention&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk with MAL&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Failure to achieve good cosmetics results&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">500 per 1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">100 per 1000 &#40;5&#8211;1000&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8 &#40;1 study&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">a</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed&#44; a full recommendation cannot be made&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Failure to improve fine lines&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20 &#40;1 study&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">c</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed&#44; a full recommendation cannot be made&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Global Photodamage failure to improve&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RR 0&#46;04 &#40;0&#46;01&#8211;0&#46;16&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">98 &#40;1 study&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed&#44; a full recommendation cannot be made&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Global Photodamage failure to improve&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RR 0&#46;19 &#40;0&#46;08&#8211;0&#46;42&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">60 &#40;1 study&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed&#44; a full recommendation cannot be made&#46;&nbsp;\t\t\t\t\t\t\n
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0055">The method of sequence generation was not reported&#46; The method used for allocation concealment was not described&#46; Measures used for blinding were not specified&#46; It was not clear if patients were blinded for satisfaction assessment&#46; Quote&#58; &#8220;A blinded investigator evaluated each side of the perioral area&#8221;&#46; All split-faces were included in the analysis&#46; Safety outcome was not specified in the methods section&#44; but was included in the analysis&#46; Only superficial wrinkles were evaluated but other photodamage features were not included&#46; Baseline characteristics of groups were not included&#46; Potential conflicts of interests and financial support were not described&#46;</p>"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0065">The method of sequence generation was not reported&#46; The method used for allocation concealment was not described&#46; It was unclear if the study was single or double-blinded&#46; A blinded investigator evaluated photodamage improvement through baseline vs post-treatment patient&#39;s photographs but blinding of side effects assessment was not specified&#46; Measures used to assure outcome assessor&#39;s blinding were not described&#46; Nine out of ten patients completed follow-ups&#46; No intention to treat analysis &#40;ITT&#41; was specified&#46; Safety outcome was not specified in the methods section&#44; but was included in the results section of the manuscript&#46; Side-effects outcomes were measured as ordinal variables but in the analysis section these were treated statistically as quantitative variables&#46; A qualitative comparison of clinical facial photodamage improvement was performed from baseline vs post-treatment in the same split-face&#44; but there were neither contralateral comparisons&#44; nor statistical comparisons for this outcome&#46; Baseline characteristics of groups were not included&#46;</p>"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0070">Sample size calculation was not specified&#46; The lack of an ITT analysis could have an impact in efficacy results due to the small sample size of the study&#46; Similarly&#44; the low power of the study might have led to non-statistical significant differences in all outcomes&#46;</p>"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0075">The risk in the intervention group &#40;and its 95&#37; confidence interval&#41; is based on the assumed risk in the comparison group and the relative effect of the intervention &#40;and its 95&#37; CI&#41;&#46; CI&#58; confidence interval&#59; RR&#58; risk ratio&#46;</p> <p class="elsevierStyleNotepara" id="npar0080">GRADE Working Group grades of evidence&#58;</p> <p class="elsevierStyleNotepara" id="npar0085">High quality&#58; we are very confident that the true effect lies close to that of the estimate of the effect&#46;</p> <p class="elsevierStyleNotepara" id="npar0090">Moderate quality&#58; we are moderately confident in the effect estimate&#58; the true effect is likely to be close to the estimate of the effect&#44; but there is a possibility that it is substantially different&#46;</p> <p class="elsevierStyleNotepara" id="npar0095">Low quality&#58; our confidence in the effect estimate is limited&#58; the true effect may be substantially different from the estimate of the effect&#46;</p> <p class="elsevierStyleNotepara" id="npar0100">Very low quality&#58; we have very little confidence in the effect estimate&#58; the true effect is likely to be substantially different from the estimate of effect&#46;</p>"
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